The physiological responses of mammals to parasitic infection is largely determined not by factors intrinsic to the invading parasite, but rather by the activity of host cells which synthesize and release a variety of cytokines and other endogenous mediators. The physiological "sum" of cellular and metabolic changes in the host that result from this interacting network of endogenous mediators must be beneficial in resolving the infection, but if this cytokine response is poorly modulated, the host can be precipitated into a potentially lethal chronic wasting syndrome known as "cachexia." Most but not all of the pathological features of cachexia can now be largely attributed to the release and activity of a single cytokine, originally identified by us as "cachectin" and now known to be identical to tumor necrosis factor (TNF). Work done during the previous grant period revealed that patients with malaria infections have elevated serum TNF levels lingering many months after their successful anti-parasitic treatment. This led to the hypothesis that the very stable malaria pigment hemozoin might be triggering TNF production in malarial infections. Preliminary studies have revealed that in contrast to all other macrophage stimulators studied to date (where TNF production is limited to the first few hours), malaria pigment induces a linear increase in TNF lasting for at least three days. This is a unique attribute of hemozoin that indicates qualitative and quantitative differences in the parasite-elicited cytokine response versus the now better known response to bacterial endotoxin. One of our major aims is to characterize the molecular mechanism underlying these differences in vitro and in vivo. Despite our own vigorous past efforts and those of a number of other investigators, neither TNF itself, nor any other known cytokine, nor any combination of known mediators can account for the induction of net muscle protein catabolism that is a hallmark of cachectic pathology. For this and other reasons, we have advanced the novel hypothesis that immune system cells, particularly macrophages, mediate the induction of net whole body nitrogen loss by upregulating their production of urea, and that the loss of muscle protein in cachexia directly reflects the consequent mobilization and catabolism of amino acids from the tissues to satisfy this irreversible depletion of available nitrogen. Thus a second major aim of this proposal is to determine the existence, consequences, and regulation of this catabolic mechanism in vivo and in vitro. Ultimately, we hope to use these mechanistic insights to devise new strategies and reagents for clinical use against the ravages of parasitic disease and its associated cachexia.